The present invention relates to the field of pharmaceuticals and, more particularly, to a formulation and a process of manufacturing stable pergolide mesylate.
Pergolide Mesylate is an ergot derivative dopamine receptor agonist at both D1 and D2 receptor sites. Pergolide mesylate is chemically designated as 8(beta)-[(Methylthio)methyl]-6-propylergoline monomethanesulfonate, and has the following structural formula: 
The formula weight of the base is 314.5; 1 mg of base corresponds to 3.18 xcexcmol.
Pergolide Mesylate is sold under the trade name PERMAX(copyright) and is provided for oral administration in tablets containing 0.05 mg (0.159 xcexcmol), 0.25 mg (0.795 xcexcmol), or 1 mg (3.18 xcexcmol) pergolide as the base. The tablets also contain croscarmellose sodium, iron oxide, lactose, magnesium stearate, and povidone. The 0.05-mg tablet also contains methionine, and the 0.25-mg tablet also contains F D and C Blue No. 2.
Pharmaceutically, pergolide mesylate is a potent dopamine receptor agonist. Pergolide is 10 to 1,000 times more potent than bromocriptine on a milligram per milligram basis in various in vitro and in vivo test systems. Pergolide mesylate inhibits the secretion of prolactin in humans; it causes a transient rise in serum concentrations of growth hormone and a decrease in serum concentrations of luteinizing hormone. In Parkinson""s disease, pergolide mesylate is believed to exert its therapeutic effect by directly stimulating post-synaptic dopamine receptors in the nigrostriatal system.
Information on oral systemic bioavailability of pergolide mesylate is unavailable because of the lack of a sufficiently sensitive assay to detect the drug after the administration of a single dose. However, following oral administration of 14C radio-labeled pergolide mesylate, approximately 55% of the administered radioactivity can be recovered from the urine and 5% from expired CO2, suggesting that a significant fraction is absorbed. Data on post absorption distribution of pergolide are unavailable.
Pergolide is approximately 90% bound to plasma proteins. This extent of protein binding may be important to consider when pergolide mesylate is co-administered with other drugs known to affect protein binding.
U.S. Pat. No. 4,797,405 which is incorporated herein by reference discloses that pergolide decomposes upon exposure to light to sulfoxide species. As a result, it is necessary to handle the compound and store the ultimate dosage form in a light-controlled environment so as to avoid a demonstrable drop in potency of the therapeutic agent. In order to retard this drop in potency, certain stabilizing agents have been incorporated into pharmaceutical compositions containing pergolide to reduce decomposition when exposed to light. Each of U.S. Pat. Nos. 4,797,405 and 5,114,948 disclose various stabilizing agents that purportedly retard decomposition to sulfoxide. However, beyond addition of stabilizing additives, the references fail to remedy the decomposition problem.
The present invention provides for stable pergolide mesylate in dry dosage form and in therapeutically effective amount without the addition of stabilizing compound. A process for manufacturing stable pergolide mesylate is also provided for both dry and wet granulates. The pergolide mesylate compound produced according to the invention is found to be substantially stable even without the presence of stabilizing compounds.
The embodiments of the present invention are described according to the following examples. The advantages of the invention are illustrated by way of comparative data in tables that follow.